This invention relates to a process for preparing certain 2-alkylthio substituted benzoic acid derivatives and their salts and esters, which are useful as intermediates in the preparation of herbicidally active compounds.
European Patent Publication No. 527036 discloses 2-methylthio-4-trifluoromethylbenzoic acid and a preparation for it. However the method described employs organolithium reagents at low temperatures which are unsuitable for large scale preparations.
The reaction to prepare 4-alkylthiosubstituted benzoate esters by the reaction of 4-halo-benzoate esters with alkyl mercaptans is known, for example as described in U.S. Pat. Nos. 1,453,885 and 5,092,919. The corresponding reaction to prepare 4-alkiylthio substituted benzoic acids by the reaction of 4-chlorobenzoic acids with alkyl mercaptans is also known, for example as reported by Beck and Yahner in J. Org. Chem. 43(10), 2052 (1978), Japanese Patent J5 8198-464 and UK Patent No. 1,453,885.
Reactions to prepare 2-alkylthio-substituted benzoic acid esters are also known for example as described in EP0560482 and WO9531446. EP0780371 also discloses the preparation of 2-alkylthio-4-trifluoromethylbenzoic acid esters. However, to the applicants knowledge there are only two references which report the displacement of a 2-halo group by alkyl mercaptans to give 2-alkylthio substituted benzoic acids, and neither of these reactions is performed using the benzoic acid as reactant. Thus F.Ruff et al. in Tetrahedron Volume 34, 2767 (1978) describes the preparation of 2-methylthio-5-nitrobenzoic acid by the reaction of methyl mercaptan with methyl 2-chloro-5-nitrobenzoate in the presence of base. In this case the 2-chlorine atom is very highly activated by the presence of the 5-nitro group. The second reference U.S. Pat. No. 3,714,179 illustrates the difficulty of displacement of the 2-fluorine atom in ethyl 2-fluorobenzoate, with the product ethyl 2-methylthiobenzoate being obtained after heating for a 3 week period.
It is desirable to provide intermediates which are used in multi-step synthetic sequences in high yields and also to develop new procedures which allow the efficient displacement of 2-halo or 2-nitro-substituted benzoic acids and their salts and esters to furnish 2-alkylthio substituted benzoic acids and their salts and esters.
It is therefore an object of this invention to provide a process for preparing 2-alkylthio substituted benzoic acids and their salts and esters proceeding in high yield, and requiring a short reaction period. The present invention allows this object to be met in whole or in part.
Thus, the present invention provides a process for the preparation of a compound of formula (I): 
wherein R represents hydrogen, or C1-6 alkyl;
R1 represents C1-6 alkyl;
R2 represents C1-6 haloalkyl, C1-6 alkyl, C1-6 haloalkoxy, C1-6 alkoxy, SOnR5 or halogen;
R4 represents hydrogen, C1-6 haloalkoxy, C1-6 alkoxy, SOnR5 or halogen; or a 5 or 6-membered heterocyclic ring (which may be unsaturated or partially saturated) containing 1 to 3 hetero atoms selected from oxygen, nitrogen and sulphur, optionally substituted by halogen, C1-6 haloalkyl, C1-6 alkyl, C1-6 haloalkoxy, C1-6 alkoxy, SOnR5, nitro or cyano;
R5 represents C1-6 alkyl; and
n represents 0, 1 or 2;
or a salt thereof: which process comprises the reaction of a compound of formula (II): 
wherein R, R2 and R4 are as hereinbefore defined, and R3 represents nitro or a halogen atom selected from fluorine, chlorine and bromine; or a salt thereof, with a compound of formula (III):
R1SXxe2x80x83xe2x80x83(III)
wherein R1 is as hereinbefore defined, and X represents hydrogen or an alkali metal.
When R4 represents a heterocyclic ring, preferred rings include 3-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 5-oxazolyl, 2-furyl, 3-furyl, 2-thienyl and 3-thienyl.
R preferably represents hydrogen, methyl or ethyl.
R1 preferably represents methyl.
R2 preferably represents trifluoromethyl.
R3 preferably represents fluorine or chlorine.
R4 preferably represents hydrogen.
X preferably represents hydrogen or a sodium, potassium or lithium atom.
When salts are used in the above reaction, preferably the salts are alkali metal salts.
In an especially preferred embodiment of the invention R1 represents C1-6 alkyl (methyl is most preferred);
R2 represents C1-6 haloalkyl (trifluoromethyl is most preferred);
R3 represents a halogen atom selected from fluorine, chlorine and bromine (fluorine or chlorine are most preferred); and
R4 represents hydrogen.
Generally the reaction of a compound of formula (II) with a compound of formula (III) is performed under substantially anhydrous conditions. It has been found that the reaction proceeds in excellent yield under such conditions.
Generally the reaction takes place with less than about 5% by volume water content, preferably less than about 2%, even more preferably less than about 1%, typically from about 0.005 to about 0.05%. It will however be understood that in certain cases slightly more or less water may be tolerated, depending on the nature of the solvents used and the temperature of the reaction, the compound of formula (I) or salt thereof to be prepared and other reaction conditions.
The reaction may be carried out using a number of solvents, but is preferably performed in a polar aprotic solvent for example N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, acetonitrile or dimethylsulphoxide. Preferred solvents are N-methylpyrrolidinone, acetonitrile or dimethylsulphoxide, the former two being preferred when the process is performed on a large scale, for reasons of cost and availability.
Where X is hydrogen. a base is preferably also present in the reaction mixture. Examples of suitable bases are alkali metal carbonates, alkoxides or hydrides such as potassium carbonate, potassium t-butoxide or sodium hydride. or amidine bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene or 1.1.3.3-tetramethylguanidine.
The reaction is generally performed at a temperature from xe2x88x9220xc2x0 C. to 150xc2x0 C. For compounds of formula (II) wherein R represents hydrogen or an alkali metal, a temperature of from about 50xc2x0 C. to about 100xc2x0 C. is preferred. For compounds of formula (II) wherein R represents C1-6 alkyl, a temperature of from about 0xc2x0 C. to about 50xc2x0 C. is preferred.
The molar ratio of the benzoic acid derivative of formula (II): alkyl thiol of formula (III) is generally from about 1:1 to about 1:2. preferably from about 1:1 to about 1:1.5, even more preferably from about 1:1.05 to about 1:1.3.
In one embodiment of the above reaction to prepare compounds of formula (I) from compounds of formula (II). R represents hydrogen or the compound of formula (II) is used in the form of a salt, preferably an alkali metal salt.
Compounds of formula (II) and (III) above are known in the literature or can be prepared using known methods.
The following non-limiting examples illustrate the invention.